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Candida auris is an emerging nosocomial fungal pathogen associated with life-threatening invasive disease due to its persistent colonization, high level of transmissibility and multi-drug resistance. Aggregative and non-aggregative growth phenotypes for C. auris strains with different biofilm forming abilities, drug susceptibilities and virulence characteristics have been described. Using comprehensive transcriptional analysis we identified key cell surface adhesins that were highly upregulated in the aggregative phenotype during in vitro and in vivo grown biofilms using a mouse model of catheter infection. Phenotypic and functional evaluations of generated null mutants demonstrated crucial roles for the adhesins Als4112 and Scf1 in mediating cell-cell adherence, coaggregation and biofilm formation. While individual mutants were largely non-aggregative, in combination cells were able to co-adhere and aggregate, as directly demonstrated by measuring cell adhesion forces using single-cell atomic force spectroscopy. This co-adherence indicates their role as complementary adhesins, which despite their limited similarity, may function redundantly to promote cell-cell interaction and biofilm formation. Functional diversity of cell wall proteins may be a form of regulation that provides the aggregative phenotype of C. auris with flexibility and rapid adaptation to the environment, potentially impacting persistence and virulence. Here, Wang et al show that Candida auris cell wall adhesins function redundantly to promote cell-cell interaction and biofilm formation as a form of regulation and potential adaption to the environment.

Candida auris , an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study investigates the calcineurin pathway in C. auris , critical for virulence and antifungal resistance in other fungal pathogens. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, comprises a catalytic subunit (Cna1) and a regulatory subunit (Cnb1) in C. auris . Our findings reveal that deletion of CNA1 or CNB1 disrupts extreme thermotolerance and cell membrane and wall integrity, leading to increased susceptibility to azoles and echinocandins. Moreover, we identified a downstream transcription factor, Crz1, which plays a central role in this pathway in other fungal species. Deletion of CRZ1 resulted in thermotolerance and membrane integrity defects comparable to those of cna1 Δ and cnb1 Δ mutants, along with increased azole susceptibility. Supporting it, fluconazole treatment induced Crz1 nuclear translocation in a Cna1-dependent manner. However, unlike cna1 Δ and cnb1 Δ mutants, the crz1 Δ mutant displayed increased resistance to echinocandins, suggesting the opposing roles for Crz1 in regulating cell wall integrity. Nevertheless, echinocandins also promoted Crz1 nuclear translocation via Cna1, underscoring the complex regulatory mechanisms at play. Cna1 was found to be required for virulence in both the Drosophila systemic infection model and the murine skin infection model. However, in a systemic murine infection model, both calcineurin and Crz1 appeared dispensable for C. auris virulence. Our findings highlight that the evolutionarily conserved calcineurin pathway employs distinct regulatory mechanisms to perform divergent roles in regulating extreme thermotolerance, cell wall and membrane integrity, antifungal drug resistance, and virulence in C. auris .

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, we show that a C. auris conserved adhesin, Als4112, is required for skin colonization via keratinocyte attachment and direct interactions with host extracellular matrix proteins, especially basement membrane proteins such as laminin. Deletion of ALS4112 reduces skin colonization in mouse models of epicutaneous and systemic infection. In addition, coating plastic and catheter surfaces with collagen I or III inhibits C. auris attachment and biofilm formation. Our study highlights the critical role of Als4112 in C. auris colonization and virulence, and explores potential strategies to reduce the pathogen’s adherence to abiotic surfaces and thus its spread in healthcare settings. Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

The rise of drug-resistant fungal species, such as Candida auris , poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris . Furthermore, the Gcn5 inhibitor CPTH 2 synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris , positioning it as a promising therapeutic target for combating invasive fungal infections. In this work, authors show that the key epigenetic regulator Gcn5 contributes to multidrug resistance in Candida auris . The inhibition of its activity by CPTH 2 synergizes with caspofungin, presenting a promising antifungal strategy.

is an emerging multidrug-resistant fungal pathogen that poses a significant global health threat. Since its discovery in 2009, has rapidly spread worldwide, causing severe infections with high mortality rates, particularly in healthcare settings. Its ability to persist in the environment, form biofilms, and resist multiple antifungal drugs underscores the urgent need to understand its pathogenicity mechanisms and associated signaling pathways. Such insights are crucial for elucidating its unique virulence traits and developing targeted therapeutic strategies. Current studies have identified several key pathways involved in its pathogenicity and antifungal drug resistance. The Ras/cAMP/PKA pathway regulates critical virulence factors, including thermotolerance, morphological plasticity, and biofilm formation. The mitogen-activated protein kinase (MAPK) and calcineurin pathways contribute to stress responses and antifungal drug resistance. The regulation of Ace2 and morphogenesis (RAM) pathway influences cell aggregation, while the target of rapamycin (TOR) pathway affects filamentous growth and biofilm development. However, the distinct characteristics of , such as its rapid environmental spread and clade-specific traits, warrant further investigation into additional signaling pathways. This review provides a comprehensive analysis of known signaling pathways associated with pathogenicity and antifungal drug resistance, integrating insights from other fungal pathogens. By synthesizing current knowledge and identifying research gaps, this review offers new perspectives on future research directions and potential therapeutic targets against this formidable pathogen.

Candida auris has globally emerged as a multidrug-resistant fungus linked to healthcare-associated outbreaks. There is still limited evidence on its virulence, pathogenicity determinants, and complex host-pathogen interactions. This study analyzes the in vivo fungal behaviour, immune response, and host-pathogen interactions upon C. auris infection compared to C. albicans and C. parapsilosis in G. mellonella. This was performed by immunolabelling fungal structures and larval plasmatocytes and using a quantitative approach incorporating bioinformatic morphometric techniques into the study of microbial pathogenesis. C. auris presents a remarkably higher immunogenic activity than expected at its moderate degree of tissue invasion. It induces a greater inflammatory response than C. albicans and C. parapsilosis at the expense of plasmatocyte nodule formation, especially in non-aggregative strains. It specifically invades the larval respiratory system, in a pattern not previously observed in other Candida species, and presents inter-phenotypic tissue tropism differences. C. auris filaments in vivo less frequently than C. albicans or C. parapsilosis mostly through pseudohyphal growth. Filamentation might not be a major pathogenic determinant in C. auris, as less virulent aggregative phenotypes form pseudohyphae to a greater extent. C. auris has important both interspecific and intraspecific virulence and phenotype heterogeneity, with aggregative phenotypes of C. auris sharing characteristics with low pathogenic species such as C. parapsilosis. Our work suggests that C. auris owns an important morphogenetic plasticity that distinguishes it from other yeasts of the genus. Routine phenotypic identification of aggregative or non-aggregative phenotypes should be performed in the clinical setting as it may impact patient management.

The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high. Candida auris , a recently emergent fungal pathogen, has caused invasive infections in health care settings worldwide. Mortality rates approach 60% and hospital spread poses a public health threat. Compared to other Candida spp., C. auris avoids triggering the antifungal activity of neutrophils, innate immune cells that are critical for responding to many invasive fungal infections, including candidiasis. However, the mechanism underpinning this immune evasion has been largely unknown. Here, we show that C. auris cell wall mannosylation contributes to the evasion of neutrophils ex vivo and in a zebrafish infection model. Genetic disruption of mannosylation pathways ( PMR1 and VAN1 ) diminishes the outer cell wall mannan, unmasks immunostimulatory components, and promotes neutrophil engagement, phagocytosis, and killing. Upon examination of these pathways in other Candida spp. ( Candida albicans and Candida glabrata ), we did not find an impact on neutrophil interactions. These studies show how C. auris mannosylation contributes to neutrophil evasion though pathways distinct from other common Candida spp. The findings shed light on innate immune evasion for this emerging pathogen. IMPORTANCE The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high. Previous study has demonstrated that neutrophils, leukocytes critical for the antifungal host defense, do not efficiently recognize and kill C. auris . Here, we show how the outer cell wall of C. auris promotes immune evasion. Disruption of this mannan polysaccharide layer renders C. auris susceptible to neutrophil killing ex vivo and in a zebrafish model of invasive candidiasis. The role of these mannosylation pathways for neutrophil evasion appears divergent from other common Candida species.

Despite the recently growing concern of pan-resistant Candida auris infection, the pathogenicity of this ascomycetous fungal pathogen and the signaling circuitries governing its resistance to antifungal drugs are largely unknown. Therefore, we analyzed the pathobiological functions of cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris , which plays conserved roles in the growth and virulence of fungal pathogens. Candida auris is a globally emerging multidrug-resistant fungal pathogen. Its pathogenicity-related signaling networks are largely unknown. Here, we characterized the pathobiological functions of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris . We focused on adenylyl cyclase ( CYR1 ), the PKA regulatory subunit ( BCY1 ), and the PKA catalytic subunits ( TPK1 and TPK2 ). We concluded that PKA acts both dependently and independently of Cyr1 in C. auris . Tpk1 and Tpk2 have major and minor roles, respectively, in PKA activity and functions. Both Cyr1 and PKA promote growth, thermotolerance, filamentous growth, and resistance to stress and antifungal drugs by regulating expression of multiple effector genes. In addition, Cyr1 and PKA subunits were involved in disinfectant resistance of C. auris . However, deletion of both TPK1 and TPK2 generally resulted in more severe defects than CYR1 deletion, indicating that Cyr1 and PKA play redundant and distinct roles. Notably, Tpk1 and Tpk2 have redundant but Cyr1-independent roles in haploid-to-diploid cell transition, which increases virulence of C. auris . However, Tpk1 and Tpk2 often play opposing roles in formation of biofilms and the cell wall components chitin and chitosan. Surprisingly, deletion of CYR1 or TPK1/TPK2 , which resulted in severe in vitro growth defects at 37°C, did not attenuate virulence, and BCY1 deletion reduced virulence of C. auris in a systemic murine infection model. In conclusion, this study provides comprehensive insights into the role of the cAMP/PKA pathway in drug resistance and pathogenicity of C. auris and suggests a potential therapeutic option for treatment of C. auris - mediated candidemia. IMPORTANCE Despite the recently growing concern of pan-resistant Candida auris infection, the pathogenicity of this ascomycetous fungal pathogen and the signaling circuitries governing its resistance to antifungal drugs are largely unknown. Therefore, we analyzed the pathobiological functions of cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris , which plays conserved roles in the growth and virulence of fungal pathogens. We show that adenylyl cyclase Cyr1 and PKA have pleiotropic roles in growth, morphogenesis, stress responses, antifungal drug and disinfectant resistance, and ploidy shifts of C. auris . Notably, however, we observed that the tpk1 Δ tpk2 Δ mutant generally exhibited more disrupted phenotypes than the cyr1 Δ mutant, and we suggest Tpk1 and Tpk2 have both cAMP-dependent and -independent roles in this pathogen. Most surprisingly, we observed that hyperactivation, not inhibition, of the cAMP/PKA pathway reduced virulence of C. auris . Based on our results, we suggest and discuss potential therapeutic strategies for candidiasis caused by C. auris .

Urinary tract infections (UTIs) are one of the most common infections, with a subgroup of these infections, catheter-associated UTIs (CAUTIs), accounting for 40% of nosocomial infections. While the majority of CAUTI pathogens are bacterial, the second most common pathogen is the fungus Candida albicans. However, in recent years, Candida auris has increasingly been isolated from urine, indicating C. auris’ potential as a urinary pathogen. C. auris has rapidly emerged as a human pathogen worldwide, becoming a serious health threat. This is of great concern due to its antifungal resistance, adherence to inanimate surfaces, high mortality rates, and the extensive knowledge gap regarding C. auris’ prevalence and pathophysiology. To understand whether C. auris is prevalent in the urinary tract, we analyzed 12,996 C. auris clinical strains and their frequency related to urine and urinary catheters. We identified urine as the second most common C. auris isolation source in the United States and the third most common worldwide. Anecdotally, C. auris urine isolates are often associated with urinary catheters and high mortality rates. Furthermore, there has been an early indication of urinary isolates developing echinocandin resistance. With the increasing incidence of uropathogenic C. auris , it is critical to have an in-depth understanding of C. auris pathogenesis in the urinary tract to effectively prevent and treat these infections.

Candida auris is an emerging multidrug-resistant skin-tropic fungal pathogen that causes serious human infections. However, the factors that regulate C. auris skin infection in vivo are still unclear. In this study, we identified that, unlike Candida albicans, which induces IL-17-secreting protective effector Th17 cells, C. auris predominately induces IFNγ-secreting pathogenic Th1 cells during reinfection. Surprisingly, we found that IFNγ enhances skin infection of C. auris but not C. albicans. Mechanistically, IFNγ enhances skin infection of C. auris by dampening the protective IL-17 responses and increasing dermal damage. Furthermore, we identified that the development of Th1 cells occurs through IL-12, produced by C. auris -induced inflammatory macrophages and monocyte-derived dendritic cells. In addition, our findings reveal that C. auris unique cell wall outer mannan layer regulates the development of Th1 and Th17 cells. Collectively, our findings, for the first time, identified that C. auris induces IFNγ to persist in the skin. These findings help explain why C. auris but not C. albicans preferentially persist in the skin long-term, with the potential to identify novel therapeutic approaches to prevent and treat this emerging fungal pathogen in humans.